Vaccination is an efficient and cost-effective form of preventing infectious diseases. However, most currently available vaccines are delivered by injection, which makes mass immunization more costly and less safe, particularly in resource-poor developing countries. Even in developed countries, patients would overwhelmingly choose to avoid injections if an alternative effective delivery system were available.
The benefits of oral vaccines go beyond just the fear of needles. Oral vaccines have several other attractive features compared with parenteral vaccines. There is always a risk that the hypodermic needle or the point of needle entry might not be properly sterilized, and oral vaccines eliminate this risk. Oral vaccines can retain potency for longer at room temperature, potentially allowing final distribution without refrigeration or at least with reduced need for refrigeration. They are also cheaper to administer because patients do not need administration by trained medical staff in a clinical setting to get their doses of vaccine. The advantages of such vaccines for society at large include faster manufacturing, ease of stockpiling and more rapid distribution to the needy. Oral vaccines can also be cheaper to produce as a result of less stringent regulatory requirements for oral preparations compared with parenteral preparations. Elimination of used needles (a byproduct of the vaccination process) can also alleviate any concerns regarding the unsafe disposal of needles, which is known to be responsible for a number of accidents.
Oral vaccination has received a great deal of attention in recent years. It is known in the art that the small intestine of mammals contains at least one main immune induction site, where antigen is processed and presented for the initiation of an immune response by the host's immune system. Lymphoid tissue associated with the small intestine allows antigen uptake at these sites and the end result is a mucosal immune response, as well as a systemic immune response. This simultaneous induction of both mucosal and systemic immunity against the antigen of interest is a well-recognized additional advantage of oral vaccination, not usually observed with subcutaneous or intramuscular vaccines that normally elicit only a systemic immune response.
Oral vaccination can also prevent some of the dangerous or fatal side-effects allegedly caused by some adjuvants commonly present in the injectable vaccine preparations, such as squalene. Adjuvants which are normally well-tolerated by the body when absorbed through the digestive system can have dangerous and fatal effects (including autoimmune arthritis and lupus) when administered by injection. A further benefit of an oral vaccine's reduced potential for side effects is the increased acceptance of vaccination within certain population groups which currently oppose vaccines on the basis of the perceived potential for harm caused by the adjuvants present in the injectable vaccines.
Also, compared to other non-injection vaccine alternatives (e.g. intranasal mist vaccination), live-viruses in intestinally administered vaccines are not known to travel into the brain and central nervous system—a rare but potentially harmful complication of intranasal vaccination.
However, oral vaccination has been regarded historically as likely to be less effective, since vaccine antigens can easily undergo digestion in the gastro-intestinal tract prior to induction of an immune response. At present, there are a limited number of oral vaccines approved for human use: the well-known polio vaccine (which is administered to infants in a drop form), a Ty21a typhoid vaccine, a cholera vaccine, a malaria vaccine, an adenovirus vaccine discontinued in 1999 (not for safety related reasons), etc. There is a large unmet market need for more oral vaccines for the prevention of infectious diseases.
It remains a challenge for an antigen to be efficiently delivered to the mucosa of the small intestine, not in small part attributable to vaccines' high susceptibility to degradation during gastric residence, due to both acidity and pepsinolytic digestion. The gastric pH is very acidic (typically between about pH 1.5 and 1.9). Under gastric conditions, acid-labile compounds typically degrade and are not readily available for downstream uptake. The protein-digesting enzyme pepsin (normally present in the stomach) will also attack and degrade a vaccine's antigens (which typically consist of fragments of proteins and peptides).
To this end, there is a need for suitable systems to ensure protection of orally-administrated immunogenic proteins from the acidic gastric environment.
The prior art response to the problem of pH sensitivity of acid labile drugs that need to be taken orally was to administer them in a dosage form that protects the drug from the acidic gastric environment. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including coatings, capsule devices, osmotic pumps, etc.
Enteric coatings are probably the most widely used method of protecting against gastric degradation. Enteric coating methods typically form a barrier around the active ingredient, with a coating that does not dissolve upon exposure to the low pH of the gastric environment. Such enteric coatings typically dissolve at a pH greater than 6, such as that found in the upper small intestine, causing the active ingredients to be released in an environment where they will not significantly degrade, and therefore can be absorbed.
However, the full-pill enteric coatings known in the art continue to have several drawbacks. There remains uncertainty as to the location at which the enteric coating starts to dissolve. Large inter- and intra-patient variations exist in such parameters as gastro-intestinal motility and pH profile, leading to a lack of control associated with the point of delivery. Some known enteric coating compositions can only be applied through the use of organic solvent-based coating solutions (e.g. acetone or chlorinated solvents) which are undesirable. Other enteric coating methods involve high temperatures of application or curing. Yet other capsules and coatings known in the art contain products derived from dead animals (gelatine) or crustaceans (chitosan), which are objected to by some users.